Diarylureas are a class of serine-threonine kinase inhibitors as well as tyrosine kinase inhibitors known in the art (Smith et al., Bioorg. Med. Chem. Lett. 2001, 11, 2775-2778, Lowinger et al., Clin. Cancer Res. 2000, 6(suppl.), 335, Lyons et al., Endocr.-Relat. Cancer 2001, 8, 219-225, Lowinger et al., Curr. Pharm. Design 2002, 8, 99-110). Omega-Carboxyaryl diphenyl ureas are disclosed in WO00/42012 and WO00/41698. In particular, it has been discovered that the diphenyl urea of formula (I),
also referred as “BAY 43-9006” or 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-amino]phenoxy}-N-methylpyridine-2-carboxamide, and its pharmaceutically acceptable salts are potent inhibitors of raf, VEGFR-2, p38, and PDGFR kinases. These enzymes are all molecular targets of interest for the treatment of hyper-proliferative diseases, including cancer. Therefore, the compound of formula (I) will be used as medicine for the treatment of the above mentioned diseases.
Despite the progress described in the art with regard to kinase inhibitors, there remains a need for improved medicines for the treatment of cancer. In particular, there remains a need for improved oral pharmaceutical compositions which can be taken in easily and therefore would increase the patient's compliance. The oral pharmaceutical composition has to provide a plasma level of the active agent which is sufficient for an effective therapy. This is dependent on the solubility and the release behavior of the active agent. In the case of a solid pharmaceutical composition the dissolution properties and chemical and mechanical stability are of importance. In order to support a high compliance the oral pharmaceutical composition should not have to be taken in more than three times a day, the less the better, and in the case of a tablet the dimensions of the tablet should not be too large to allow a good swallowing. The dimensions of a tablet are dependent on the amount of the active agent needed for an effective therapy and the amounts of the excipients. Type and amount of the excipients in combination with the process for preparing are essential for release properties, bioavailability of the compound in mammals, stability and the industrial applicability of the manufacturing process of the pharmaceutical composition.
The objective of the present invention is to provide a pharmaceutical composition comprising the compound of formula (I) which should be applied no more then three times a day in order to achieve an effective plasma level of the compound of formula (I). In the case of a tablet or capsule as oral pharmaceutical composition it should not be too large to provide good swallowing and no more than two should have to be taken in at the same time.